| Autor: |
Wakley AA; Department of Biomedical Sciences, College of Osteopathic Medicine, University of New England, Biddeford, ME 04005.; Center for Excellence in the Neurosciences, University of New England, Biddeford, ME 04005., Leeming R; Center for Excellence in the Neurosciences, University of New England, Biddeford, ME 04005.; Department of Biology, College of Arts and Sciences, University of New England, Biddeford, ME 04005., Malon J; Department of Biomedical Sciences, College of Osteopathic Medicine, University of New England, Biddeford, ME 04005.; Center for Excellence in the Neurosciences, University of New England, Biddeford, ME 04005., Arabatzis TJ; Center for Excellence in the Neurosciences, University of New England, Biddeford, ME 04005.; Department of Biology, College of Arts and Sciences, University of New England, Biddeford, ME 04005., Yuen Koh W; Department of Mathematical Sciences, College of Arts and Sciences, University of New England, Biddeford, ME 04005., Cao L; Department of Biomedical Sciences, College of Osteopathic Medicine, University of New England, Biddeford, ME 04005.; Center for Excellence in the Neurosciences, University of New England, Biddeford, ME 04005. |
| Abstrakt: |
CD137L (4-1BBL) is a costimulatory molecule whose signaling can promote monocyte/macrophage functions; however, CD137L-mediated microglial response and its role in neuropathic pain remain unknown. We investigated CD137L following peripheral nerve injury-induced neuropathic pain using a spinal nerve L5 transection (L5Tx) murine model in both sexes. First, C57BL/6_CD137L knock-out (KO) mice displayed decreased mechanical and diminished heat hypersensitivity compared to wild-type (WT) controls, beginning on day 3 to up to day 35 post-L5Tx. Purified anti-mouse CD137L neutralizing monoclonal antibody (0.1 or 0.5 µg) was also used to identify CD137L's window of action in BALB/c mice. Anti-CD137L antibody was intrathecally administered either from day 0 (before surgery) to day 7 (early treatment), or from day 6 to 13 post-L5Tx (late treatment), and nociceptive thresholds were assessed before surgery to up to day 35 post-surgery. Early treatment with anti-CD137L reduced L5Tx-induced mechanical but not heat hypersensitivity, while later treatment did not alter either sensitivity. Pro- versus anti-inflammatory responses within the lumbar spinal cord following L5Tx were further evaluated via quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC) in time-course studies. Following L5Tx, female CD137L KO mice did not show increased iNOS mRNA and had reduced numbers of IL-1β + cells compared to WT. At 21 d post-surgery, CD137L KO mice had higher total numbers of arginase (Arg)-1 + cells and Arg-1 + microglia. Altogether, results indicate that spinal cord CD137L contributes to the development of peripheral nerve injury-induced neuropathic pain, which may be in part mediated through CD137L's modulation of the pro- and anti-inflammatory balance within the spinal cord. |
